Updated survival outcomes from the EMBER-3 trial reinforced the clinical benefit of imlunestrant as monotherapy and in combination with abemaciclib as oral, chemotherapy-free treatment options for patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) advanced or metastatic breast cancer.
Breast medical oncologist Komal Jhaveri, MD, FACP, FASCO, International Study Chair and member of the steering committee for EMBER-3, and principal investigator of the study at Memorial Sloan Kettering Cancer Center (MSK), presented the latest results in a late-breaking presentation at the San Antonio Breast Cancer Symposium (SABCS) on December 12, 2025. Dr. Jhaveri was also the lead and corresponding author of the paper published simultaneously in the Annals of Oncology. (1)
“Imlunestrant monotherapy extended median overall survival by 11.4 months versus endocrine therapy in patients with ESR1-mutated ER+/HER2- disease,” said Dr. Jhaveri, Associate Attending, Breast Medicine and Early Drug Development Services and Section Head of the Endocrine Therapy Research Program at MSK. “Additionally, in all patients, imlunestrant plus abemaciclib achieved a median progression-free survival (PFS) of 10.9 months, demonstrated a favorable OS trend with a hazard ratio of less than 1, and extended the time to chemotherapy by more than a year.”
The EMBER-3 results with imlunestrant plus abemaciclib continue to represent the largest PFS advantage reported to date for patients with ER+/HER2- advanced breast cancer.
Study Design
Imlunestrant is an oral, brain penetrant, selective estrogen receptor degrader and pure ER antagonist that delivers continuous ER inhibition. It was designed as an oral medication to be more convenient than fulvestrant, which is administered via intramuscular injection.
The EMBER series of trials have been evaluating imlunestrant monotherapy and then in combination with abemaciclib, an oral CDK4/6 inhibitor. MSK has been involved from the beginning, collaborating with the manufacturer on the drug development plan. Dr. Jhaveri was principal investigator of the phase 1 EMBER trial (1) and is the co-chair and a member of the steering committee for EMBER-4 (NCT05514054), which is evaluating adjuvant imlunestrant as part of the drug development strategy and has completed accrual for 8,000 patients.
Abemaciclib was approved in the metastatic setting both as a single agent and with endocrine therapy, including fulvestrant in 2018. (3)
The present EMBER-3 study was a phase 3, open-label, randomized controlled trial for patients with ER+/HER2- advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy (NCT04975308). It was conducted at 195 international sites in 22 countries, with an estimated final completion date of August 2027. A total of 874 patients were randomized to receive imlunestrant (n=331), standard endocrine therapy (fulvestrant or exemestane, n=330), or imlunestrant plus abemaciclib (n=213). (1)
The primary endpoint was progression-free survival (PFS) for imlunestrant monotherapy versus standard-of-care endocrine therapy in patients with ESR1-mutations and all patients, and for imlunestrant plus abemaciclib versus imlunestrant in concurrently randomized patients. Overall survival (OS) was a key secondary endpoint, tested only if the corresponding PFS reached statistical significance. (1)
Updated Study Results
With an additional 14-month follow-up (median follow-up 28.5 months), 10% of patients remained on treatment as of the data cut-off of August 18, 2025.
In patients with ESR1-mutated ER+/HER2- advanced breast cancer, the median OS was 34.5 months for imlunestrant monotherapy versus 23.1 months for standard-of-care endocrine therapy, an extension of 11.4 months (hazard ratio (HR) = 0.60, p = 0.0043). (1)
In all patients, regardless of ESR1 mutations, median OS was not reached with imlunestrant-abemaciclib and 34.4 months with imlunestrant monotherapy (HR = 0.82, p = 0.2622). Note that OS data are not yet mature (33% maturity). (1)
PFS was 10.9 months for imlunestrant-abemaciclib versus 5.5 months with imlunestrant alone (HR = 0.59, p < 0.001). (1)
Imlunestrant regimens also delayed time to chemotherapy for patients with ESR1 mutations by 5.5 months in the monotherapy group and 12.2 months in the combination group, regardless of ESR1 mutations. (1)
“An extended delay in chemotherapy initiation is particularly meaningful for patients with advanced breast cancer because chemotherapy often negatively affects their quality of life,” said Dr. Jhaveri.
Previous Efficacy Results
The primary analysis for EMBER-3 showed a significant PFS benefit with imlunestrant versus standard-of-care endocrine therapy in patients with ESR1-mutated advanced breast cancer. This was presented at SABCS 2024 and published simultaneously in December 2024 in The New England Journal of Medicine. (4)
Based on this result, the U.S. Food and Drug Administration (FDA) approved imlunestrant monotherapy and the Guardant360 CDx assay as a companion diagnostic device for this patient population on September 25, 2025. (5)
The primary analysis also showed a significant PFS benefit for imlunestrant plus abemaciclib versus imlunestrant alone in all patients, regardless of ESR1-mutation status: the median PFS for imlunestrant-abemaciclib was 9.4 months versus 5.5 months for imlunestrant alone (HR = 0.57, p < 0.001). (4) OS data for imlunestrant monotherapy was 31% mature for patients with ESR1 mutations, 23% for all patients, and demonstrated a favorable trend. OS data for imlunestrant plus abemaciclib was 15% mature. (4)
Next Steps
Given the encouraging potential of the all-oral imlunestrant plus abemaciclib combination, Eli Lilly and Company has submitted the combination data for U.S. regulatory review in ESR1-mutated metastatic breast cancer.
“The National Comprehensive Cancer Network is also in the process of reviewing these results with a view to include imlunestrant regimens in clinical practice guidelines for patients with ER+/HER2- advanced or metastatic breast cancer,” said Dr. Jhaveri.
“Currently, the five-year survival for patients with distant disease is about 35%. Imlunestrant regimens provide clinically meaningful efficacy and new hope for this patient population,” Dr. Jhaveri said.
The study was sponsored by Eli Lilly and Company. Dr. Jhaveri is supported by a National Institutes of Health/National Cancer Institute Cancer Center Grant to MSK (P30 CA008748). Access disclosures for Dr. Jhaveri.
Read our previous coverage of the EMBER-3 trial from SABCS 2024. Learn more about breast cancer clinical trials at MSK.